@article {Wrighteaar5536,
author = {Wright, Shane C. and Ca{\~n}izal, Maria Consuelo Alonso and Benkel, Tobias and Simon, Katharina and Le Gouill, Christian and Matricon, Pierre and Namkung, Yoon and Lukasheva, Viktoria and K{\"o}nig, Gabriele M. and Laporte, St{\'e}phane A. and Carlsson, Jens and Kostenis, Evi and Bouvier, Michel and Schulte, Gunnar and Hoffmann, Carsten},
title = {FZD5 is a Gαq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs},
volume = {11},
number = {559},
elocation-id = {eaar5536},
year = {2018},
doi = {10.1126/scisignal.aar5536},
publisher = {Science Signaling},
abstract = {Despite exhibiting sequence and structural similarity to other classes of G protein{\textendash}coupled receptors (GPCRs), class F family members are generally not considered to be prototypical GPCRs. Wright et al. found that the class F GPCR FZD5 exhibited many of the functional characteristics of GPCRs. FZD5 underwent a conformational change similar to that of conventional GPCRs upon ligand binding. Ligand binding also caused FZD5 to activate signaling through Gαq-containing heterotrimeric G proteins. FZD5-mediated activation of Gαq elicited the production of second messengers, the activation of kinases, and cellular responses typical of G protein activation by classical GPCRs. These findings suggest that FZD5 and other class F GPCRs may not differ from prototypical GPCRs as much as was previously thought.Frizzleds (FZDs) are a group of seven transmembrane{\textendash}spanning (7TM) receptors that belong to class F of the G protein{\textendash}coupled receptor (GPCR) superfamily. FZDs bind WNT proteins to stimulate diverse signaling cascades involved in embryonic development, stem cell regulation, and adult tissue homeostasis. Frizzled 5 (FZD5) is one of the most studied class F GPCRs that promote the functional inactivation of the β-catenin destruction complex in response to WNTs. However, whether FZDs function as prototypical GPCRs has been heavily debated and, in particular, FZD5 has not been shown to activate heterotrimeric G proteins. Here, we show that FZD5 exhibited a conformational change after the addition of WNT-5A, which is reminiscent of class A and class B GPCR activation. In addition, we performed several live-cell imaging and spectrometric-based approaches, such as dual-color fluorescence recovery after photobleaching (dcFRAP) and resonance energy transfer (RET){\textendash}based assays that demonstrated that FZD5 activated Gαq and its downstream effectors upon stimulation with WNT-5A. Together, these findings suggest that FZD5 is a 7TM receptor with a bona fide GPCR activation profile and suggest novel targets for drug discovery in WNT-FZD signaling.},
issn = {1945-0877},
URL = {http://stke.sciencemag.org/content/11/559/eaar5536},
eprint = {http://stke.sciencemag.org/content/11/559/eaar5536.full.pdf},
journal = {Science Signaling}
}